This invention relates to gene delivery. More particularly, this invention relates to linear polyethylenimine-sterol conjugates as carriers for gene delivery.
Polyethylenimine (PEI) has long been used as a carrier for non-viral gene delivery, however, the ideal molecular weight and geometry of PEI for gene delivery have not been determined. A. von Harpe et al., 69 J. Control. Release 309-322 (2000). Typical molecular weights of PEI vary from about 423 to about 800,000, with linear and branched geometries. Linear PEI (LPEI) (MW 423) cannot efficiently buffer the low pH found in the secondary lysosome after endocytosis. Consequently, the need for a co-lipid to facilitate the release of plasmid DNA (pDNA) has been shown. D. Y. Furgeson, R. N. Cohen, R. I. Mahato & S. W. Kim, 19 Pharm. Res. 382-390 (2002). However, LPEI (MW 25,000) has over 520 secondary amines capable of protonation and subsequent pH buffering. Therefore, the higher molecular weight polymers do not require a co-lipid for release of plasmid DNA from endosomes. LPEI has been shown to be an effective non-viral gene carrier, D. Goula et al., 5 Gene Ther. 712-717 (1998); J. L. Coll et al., 10 Hum. Gene Ther. 1659-1666 (1999); P. Chollet et al., 4 J. Gene Med. 84-91 (2002); D. Goula et al., 7 Gene Ther. 499-504 (2000); S. M. Zou et al., 2 J. Gene Med. 128-134 (2000); A. N. Uduehi et al., 4 Mol. Ther. 52-57 (2001); L. Wightman et al., 3 J. Gene Med. 362-372 (2001); S. Brunner et al., 5 Mol. Ther. 80-86 (2002); R. Kircheis et al., 9 Cancer Gene Ther. 673-680 (2002), with increased gene expression and decreased toxicity compared to branched PEI (BPEI). The putative method of PEI gene expression is through endosomal release by osmotic swelling by the proton sponge effect. O. Boussif et al., 92 Proc. Nat'l Acad. Sci. USA 7297-7301 (1995).
Thus, while prior art gene carriers are known and are generally suitable for their limited purposes, they possess certain inherent deficiencies that detract from their overall utility for gene delivery.
In view of the foregoing, it will be appreciated that providing linear polyethylenimine-sterol conjugates as gene carriers would be a significant advancement in the art.